H3 histamine receptors provide feedback inhibition of synthesis and release of histamine from the hypothalamus, as well as, inhibition of the release of other neurotransmitters, such as acetylcholine from intestinal cholinergic nerves, and norepinephrine from the retina and cerebral cortex. Preliminary data indicate that the ability of H3 receptors to regulate feedback inhibition of histamine release in spontaneously hypertension rats is age-dependent. Our central hypothesis is sustained hypertension enhances H3-receptor's ability to regulate the synthesis and release of histamine in the CNS. To test this hypothesis we will: 1) assess changes in the evoked-release of histamine in the CNS (hypothalamus); 2) investigate quantitatively, changes in H3-histaminergic receptors in the CNS (hypothalamus); and 3) identify changes in the expression of H3 receptor mRNAs in the CNS (hypothalamus) using RT-PCR during the progression of hypertension. The proposed studies will be conducted in the CNS of spontaneously hypertensive (SHR) phenotypes and compared with normotensive (WKY) rats-accepted models for essential hypertension during the progession of hypertension. The results/data obtained will define the role of histamine in the development of hypertension and the function of the H3 receptor in upregulation or downregulation of histamine. The information generated from this investigation will also provide important insights into the pathophysiological causes of hypertension and could offer an opportunity to develop potential new drugs for the management of hypertension.